The broad objective of this project is to contribute towards the elucidation of the biochemistry and physiology of the beta cells of the Islets of Langerhans. This includes an understanding of the ways in which the structure and metabolism of these cells are geared to the synthesis and secretion of insulin and the mechanisms by which their activity is modulated by external factors such as blood sugar, hormones, and drugs. We have been using the toadfish in our studies since in this species, in contrast to mammals, the islet of Langerhans is segregated into a discrete mass which is separated from the pancreatic acinar tissue. We are examining the uptake of different substrates by the islet, concentrating particularly on characterizing the sugar transport system we have shown to be present. The mechanism by which glucose triggers insulin secretion from islet cells in vitro and from isolated insulin storage granules is also being studied, as are the enzymatic composition and metabolic pathways of islet tissue. Our study of the mechanism of the diabetogenic action of alloxan is another approach to achieving the overall objective; understanding the basis of the selectivity of alloxan for beta cells could provide significant information on the unique properties of these cells which enable them to carry out their specific functions. We have shown that alloxan increases the permeability of islet tissue in vitro and our evidence indicates that it does so by reacting with essential sulfhydryl groups at the sugar transport site in the beta cell membrane. Therefore, we are presently attempting to define the exact nature of these groups and the way in which they differ from the sulfhydryl groups in membranes of other cells; for example we are comparing, in islet and other tissues, the reactivity of these groups with a number of sulfhydryl reagents under a variety of conditions, and testing the ability of various thiols and sugars to protect against and reverse the action of these reagents.